Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?
Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women.


Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults.
To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression. In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years). There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006). Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT.


Circadian rest-activity disturbances in seasonal affective disorder.
Previous studies hypothesized that seasonal affective disorder (SAD) was caused by a circadian rhythm abnormality. The purpose of this study was to ascertain whether rest-activity rhythms were phase delayed, diminished in amplitude, or more poorly entrained to the 24-hour day. Twenty healthy adult controls and 25 outpatients meeting Rosenthal-National Institute of Mental Health criteria for SAD and DSM-III-R criteria for major or bipolar depression with seasonal pattern had their levels of activity recorded for 72 hours (weekdays) using wrist-worn actigraphs. Subjects with SAD had activity levels that were 11% lower than controls (P = .03), and their levels of activity were most attenuated during the first 2 hours after arising (P = .004). The relative amplitude of the circadian rhythm did not differ between groups. Patients with SAD were phase delayed by 50 minutes for the entire period (P = .02). Analysis of each individual day indicated that patients were delayed by up to 70 minutes (P = .007). Interdaily stability, an index of coupling between the rhythm and its zeitigeber was reduced in SAD (P = .01). Compared with controls, patients with SAD had best-fit circadian periods that were 92% more deviated from 24 hours (P = .007) and daily acrophase (time of the peak of the fit circadian rhythm) times that were 110% more variable between days (P < .001). Patients with SAD have circadian rest-activity rhythms that are significantly phase delayed and more poorly entrained to the 24-hour day.


Biofuels and biodiversity.
The recent increase in liquid biofuel production has stemmed from a desire to reduce dependence on foreign oil, mitigate rising energy prices, promote rural economic development, and reduce greenhouse gas emissions. The growth of this industry has important implications for biodiversity, the effects of which depend largely on which biofuel feedstocks are being grown and the spatial extent and landscape pattern of land requirements for growing these feedstocks. Current biofuel production occurs largely on croplands that have long been in agricultural production. The additional land area required for future biofuels production can be met in part by reclaiming reserve or abandoned croplands and by extending cropping into lands formerly deemed marginal for agriculture. In the United States, many such marginal lands have been enrolled in the Conservation Reserve Program (CRP), providing important habitat for grassland species. The demand for corn ethanOl has changed agricultural commodity economics dramatically, already contributing to loss of CRP lands as contracts expire and lands are returned to agricultural production. Nevertheless, there are ways in which biofuels can be developed to enhance their coexistence with biodiversity. Landscape heterogeneity can be improved by interspersion of land uses, which is easier around facilities with smaller or more varied feedstock demands. The development of biofuel feedstocks that yield high net energy returns with minimal carbon debts or that do not require additional land for production, such as residues and wastes, should be encouraged. Competing land uses, including both biofuel production and biodiversity protection, should be subjected to comprehensive cost-benefit analysis, so that incentives can be directed where they will do the most good.


Generation of Transmission-Competent Human Malaria Parasites with Chromosomally-Integrated Fluorescent Reporters.
Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.


Observation-to-imitate plus practice could add little to physical therapy benefits within 31 days of stroke: translational randomized controlled trial.
Observation of action with intention-to-imitate (OTI) might enhance motor recovery. This early phase trial investigated whether OTI followed by physical practice (OTI + PP) enhanced the benefits of conventional physical therapy (CPT) on upper limb recovery early after stroke. Participants were 3 to 31 days poststroke. They had substantial paresis and ability to imitate action with their ipsilesional arm. After baseline measures, participants were randomized to either OTI + PP in addition to CPT or to CPT only. Outcome measures were made after 15 days of treatment. The measurement battery was the Motricity Index (MI) and the Action Research Arm Test (ARAT). Change, baseline to outcome, was examined using the Wilcoxon test for within group and Mann-Whitney U test for between groups. Sixty-five of 570 stroke survivors were eligible, 55 were able to imitate, 37 gave informed consent, 7 were transferred out of area before baseline, and 29 were randomized. Outcome measures were completed with 13 CPT participants and 9 OTI + PP participants. Both groups showed statistically significant improvements for the MI (CPT median change 8, P = .003; OTI + PP median change 10, P = .012) but the median (95% confidence interval [CI]) between-group difference was 0.0 (-11, 16), P = 1.000. For the ARAT, only the CPT group showed a statistically significant improvement (median 9, P = .006). The median (95% CI) between-group difference of 1.0 (-18, 23) was not statistically significant (P = .815). These findings suggest that OTI + PP might add little to the benefits of CPT early after stroke.


Apolipoprotein B 3' hypervariable repeat genotype: association with plasma lipid concentration, coronary artery disease, and other restriction fragment polymorphisms.
Apolipoprotein B gene 3' variable number tandem repeat (VNTR) and related regions were amplified by PCR and analyzed by agarose gel electrophoresis. Eighteen VNTR alleles (VNTR25, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 58, 60) and 45 genotypes were observed in 477 Taiwanese subjects. The VNTR35 allele and genotype VNTR35/35 were observed most frequently in this population. The polymorphism information content was 0.62. Some minor alleles, such as VNTR25 and 60, were found only in coronary artery disease (CAD) and stroke patients in our sampling, and no statistically significant difference was observed in VNTR allelic frequency between control and CAD or stroke patients. Significant differences in allelic distribution of some VNTR alleles were observed between our normal Taiwanese population and a Caucasian group studied by others. VNTR43-47 and AluI+ (coding Ala591) restriction fragment length polymorphism (RFLP) as well as VNTR49-60 and EcoRI- (coding Lys4154) RFLP were found to be highly coinherited. No apparent association between the VNTR genotype and plasma lipid concentration was observed; however, for the same genotype, the CAD and stroke patients frequently showed higher lipoprotein(a) and lower HDL cholesterol concentrations than the control group.


Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development.
Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. Using tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin-NFAT signals within a narrow time window at embryonic Day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)-Alk5 signalling to control coronary development. Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFβ signalling during embryonic development.


Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery.
Glucocorticoids are given for sensorineural hearing loss, but little is known of their molecular impact on the inner ear. Furthermore, in spite of claims of improved hearing recovery with intratympanic delivery of steroids, no studies have actually documented the inner ear molecular functions that are enhanced with this delivery method. To assess steroid-driven processes in the inner ear, gene chip analyses were conducted on mice treated systemically with the glucocorticoids prednisolone or dexamethasone or the mineralocorticoid aldosterone. Other mice were given the same steroids intratympanically. Inner ears were harvested at 6 hours and processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34 000 genes. Results were statistically analyzed for up or down expression of each gene against control (untreated) mice. Analyses showed approximately 17 500 genes are normally expressed in the inner ear and steroids alter expression of 55% to 82% of these. Dexamethasone changed expression of 9424 (53.9%) inner ear genes following systemic injection but 14 899 ear genes (85%) if given intratympanically. A similar pattern was seen with prednisolone, as 7560 genes were impacted by oral delivery and 11 164 genes (63.8%) when given intratympanically. The mineralocorticoid aldosterone changed expression of only 268 inner ear genes if given orally, but this increased to 10 124 genes (57.9%) if injected intratympanically. Furthermore, the glucocorticoids given actually impacted more inner ear genes via the mineralocorticoid receptor than the glucocorticoid receptor. Thousands of inner ear genes were affected by steroids, and this number increased significantly if steroids were delivered intratympanically. Also, the impact of glucocorticoids on inner ear mineralocorticoid functions is more substantial than previously known. Thus, the application of therapeutic steroids for hearing loss needs to be reassessed in light of their more comprehensive impact on inner ear genes. Furthermore, simply ascribing the efficacy of steroids to immunosuppression no longer appears to be warranted.


Ethnohistorical evidence for inbreeding among the pre-Hispanic Mixtec royal caste.
Pre-Columbian Mixtec social organization was distinguished by the tight endogamy of the ruling class, which included many consanguineous marriages. It was also characterized by a vigorous historical and genealogical tradition. The historical documents, or codices, provide materials for the calculation of the levels of inbreeding present before the Spanish Conquest. A genealogical analysis of inbreeding was performed on the combined pedigree, which spanned the tenth through sixteenth centuries, of all individuals connected by ancestry, descent, or marriage with Lord 8 Deer Jaguar Claw of Tilantongo (A.D. 1063-1115). Sixty of the 217 couples (27.65%) were consanguineous. When only couples of wholly known grandparentage were considered (N = 39), F = 0.1051. The mean F of all couples, even those where one spouse was of unknown parentage, was 0.0243. Over the 550 years of the pedigree the maximum F in any 52-year period was 0.1324. This level of inbreeding is sufficient to produce noticeable effects on population structure and affinities over time.


High-throughput proteomic analysis of formalin-fixed paraffin-embedded tissue microarrays using MALDI imaging mass spectrometry.
A novel method for high-throughput proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissue microarrays (TMA) is described using on-tissue tryptic digestion followed by MALDI imaging MS. A TMA section containing 112 needle core biopsies from lung-tumor patients was analyzed using MS and the data were correlated to a serial hematoxylin and eosin (H&E)-stained section having various histological regions marked, including cancer, non-cancer, and normal ones. By correlating each mass spectrum to a defined histological region, statistical classification models were generated that can sufficiently distinguish biopsies from adenocarcinoma from squamous cell carcinoma biopsies. These classification models were built using a training set of biopsies in the TMA and were then validated on the remaining biopsies. Peptide markers of interest were identified directly from the TMA section using MALDI MS/MS sequence analysis. The ability to detect and characterize tumor marker proteins for a large cohort of FFPE samples in a high-throughput approach will be of significant benefit not only to investigators studying tumor biology, but also to clinicians for diagnostic and prognostic purposes.


Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages.
Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-β (TRIF) protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-β and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.


Distinct OGT-Binding Sites Promote HCF-1 Cleavage.
Human HCF-1 (also referred to as HCFC-1) is a transcriptional co-regulator that undergoes a complex maturation process involving extensive O-GlcNAcylation and site-specific proteolysis. HCF-1 proteolysis results in two active, noncovalently associated HCF-1N and HCF-1C subunits that regulate distinct phases of the cell-division cycle. HCF-1 O-GlcNAcylation and site-specific proteolysis are both catalyzed by O-GlcNAc transferase (OGT), which thus displays an unusual dual enzymatic activity. OGT cleaves HCF-1 at six highly conserved 26 amino acid repeat sequences called HCF-1PRO repeats. Here we characterize the substrate requirements for OGT cleavage of HCF-1. We show that the HCF-1PRO-repeat cleavage signal possesses particular OGT-binding properties. The glutamate residue at the cleavage site that is intimately involved in the cleavage reaction specifically inhibits association with OGT and its bound cofactor UDP-GlcNAc. Further, we identify a novel OGT-binding sequence nearby the first HCF-1PRO-repeat cleavage signal that enhances cleavage. These results demonstrate that distinct OGT-binding sites in HCF-1 promote proteolysis, and provide novel insights into the mechanism of this unusual protease activity.


The relationship between inpatient fluoroquinolone use and Clostridium difficile-associated diarrhea.
Limited evidence suggests there may be a link between fluoroquinolone use and Clostridium difficile-associated diarrhea (CDAD), but such an association remains unclear due to conflicting data. To determine the relationship between inpatient fluoroquinolone use and CDAD; secondary objectives included the relationship between CDAD and fluoroquinolone selection, duration of therapy, and route of administration, as well as the association between fluoroquinolones and CDAD complications. We conducted a retrospective, case-control study of adult inpatients diagnosed with CDAD during the period of July 2007-July 2008. In total, 174 case patients were matched on a 1:1 basis with controls. A thorough assessment of all inpatient antibiotic use was conducted, including regimens administered at our institution within the previous 8 weeks. Odds ratios were calculated using univariate logistic-regression analysis. Use of fluoroquinolones was not significantly different between patients with CDAD and matching controls (OR 1.36; 95% CI 0.09 to 2.10; p = 0.16). No relationship was found between CDAD and the individual fluoroquinolones: ciprofloxacin (OR 1.36; 95% CI 0.87 to 2.12; p = 0.18), levofloxacin (OR 1.17; 95% CI 0.62 to 2.22; p = 0.63), and moxifloxacin (OR 1.34; 95% CI 0.81 to 2.20; p = 0.25). Fluoroquinolone route of administration did not differ significantly between groups for patients receiving intravenous (OR 1.20; 95% CI 0.74 to 1.94; p = 0.46) or oral (OR 0.79; 95% CI 0.44 to 1.44; p = 0.45) therapy. Complications from CDAD were not significantly increased by fluoroquinolone use (OR 1.37; 95% CI 0.72 to 2.61; p = 0.35). Inpatient administration of fluoroquinolones was not associated with CDAD at our institution. Fluoroquinolone use in patients who developed CDAD was not related to higher incidences of CDAD-related complications.


Hexosamine Biosynthetic Pathway Inhibition Leads to AML Cell Differentiation and Cell Death.
Treatment for acute myeloid leukemia (AML) has remained unchanged for past 40 years. Targeting cell metabolism is a promising avenue for future cancer therapy. We found that enzymes involved in metabolic hexosamine biosynthetic pathway (HBP) are increased in patients with AML. Inhibiting GFAT (the rate-limiting enzyme of HBP) induced differentiation and apoptosis in AML cells, sparing normal cells. UDP-GlcNAc, the end product of HBP, is the substrate for O-GlcNAcylation, a posttranslational modification. O-GlcNAc transferase (OGT) is the enzyme which transfers GlcNAc from UDP-GlcNAc to target proteins. Inhibition of O-GlcNAcylation, using OGT inhibitors as well as genetic knockdown of OGT, also led to cell differentiation and apoptosis of AML cells. Finally, HBP inhibition in vivo reduced the tumor growth in a subcutaneous AML xenograft model and tumor cells showed signs of differentiation in vivo A circulating AML xenograft model also showed clearance of tumor load in bone marrow, spleen, and blood, after HBP inhibition, with no signs of general toxicity. This study reveals an important role of HBP/O-GlcNAcylation in keeping AML cells in an undifferentiated state and sheds light into a new area of potential AML therapy by HBP/O-GlcNAc inhibition. Mol Cancer Ther; 17(10); 2226-37. ©2018 AACR.


DNA methylation changes in response to ocean acidification at the time of larval metamorphosis in the edible oyster, Crassostrea hongkongensis.
Unprecedented rate of increased CO2 level in the ocean and the subsequent changes in carbonate system including decreased pH, known as ocean acidification (OA), is predicted to disrupt not only the calcification process but also several other physiological and developmental processes in a variety of marine organisms, including edible oysters. Nonetheless, not all species are vulnerable to those OA threats, e.g. some species may be able to cope with OA stress using environmentally induced modifications on gene and protein expressions. For example, external environmental stressors including OA can influence the addition and removal of methyl groups through epigenetic modification (e.g. DNA methylation) process to turn gene expression "on or off" as part of a rapid adaptive mechanism to cope with OA. In this study, we tested the above hypothesis through testing the effect of OA, using decreased pH 7.4 as proxy, on DNA methylation pattern of an endemic and a commercially important estuary oyster species, Crassostrea hongkongensis at the time of larval habitat selection and metamorphosis. Larval growth rate did not differ between control pH 8.1 and treatment pH 7.4. The metamorphosis rate of the pediveliger larvae was higher at pH 7.4 than those in control pH 8.1, however over one-third of the larvae raised at pH 7.4 failed to attach on optimal substrate as defined by biofilm presence. During larval development, a total of 130 genes were differentially methylated across the two treatments. The differential methylation in the larval genes may have partially accounted for the higher metamorphosis success rate under decreased pH 7.4 but with poor substratum selection ability. Differentially methylated loci were concentrated in the exon regions and appear to be associated with cytoskeletal and signal transduction, oxidative stress, metabolic processes, and larval metamorphosis, which implies the high potential of C. hongkongensis larvae to acclimate and adapt through non-genetic ways to OA threats within a single generation.


A comparison of five transition programmes for youth with chronic illness in Canada.
Adolescents with chronic illnesses who are transferred from the paediatric healthcare setting to adult care often get lost in the system, resulting in poorer long-term health outcomes. The Canadian Pediatric Society and the Society of Adolescent Health and Medicine have position papers on the key elements recommended for transition programmes. A comparison of five transition programmes for youth with chronic illness in Canada is presented with a discussion of how they reflect these guidelines. The process used to review the content and effectiveness can provide others with a framework for learning about existing transition programmes to assist them in developing their own.


Exploring Tourniquet Conversion in Simulation to Develop Concepts and Hypotheses.
Compared with those of tourniquet application, tourniquet conversion concepts are underdeveloped. The purpose of this project was to develop tourniquet conversion concepts and generate hypotheses. One person performed 100 tests of tourniquet application and conversion. Testing varied by conversion types, materials, and assessments. Conversions were from improvised or Combat Application Tourniquets (C-A-T) to another C-A-T, a new site (with initial C-A-T only), a pneumatic Emergency and Military Tourniquet (EMT), or a pressure dressing (compression bandage or a roll gauze and an elastic wrap). Simulated limbs were created using plastic bottle-based manikins, pool noodle-based manikins, plastic pipes, glass bottles, a rain downspout, and a cardboard poster tube. Tourniquet application, conversion, and total times averaged 105, 132, and 237 seconds, respectively. Improvised tourniquet time was longer than that of C-A-T (p ≤ .05, all three). By initial tourniquet site, the 2-3 inches site had longer conversion and total time (p ≤ .02, both) compared with highest site. By whether initial tourniquets placed were also used in conversion, total time was shorter if yes (p = .05). Conversion to a pressure dressing was longer in conversion and total time (p ≤ .02, both) compared with conversion to a tourniquet. One wrap was short; we switched to those longer to cover limbs better. Limb types varied for indentation. Conversion communications improved when we used abbreviations and symbols. This preliminary project simulated tourniquet conversion to develop clinical concepts and research hypotheses to build a better basis for later research.


Combination of UV absorbance and electron donating capacity to assess degradation of micropollutants and formation of bromate during ozonation of wastewater effluents.
In this study, the changes in UV absorbance at 254 nm (UVA254) and electron donating capacity (EDC) were investigated as surrogate indicators for assessing removal of micropollutants and bromate formation during ozonation of wastewater effluents. To measure the EDC, a novel method based on size exclusion chromatography followed by a post-column reaction was developed and calibrated against an existing electrochemical method. Low specific ozone doses led to a more efficient abatement of EDC than of UVA254. This was attributed to the abatement of phenolic moieties in the dissolved organic matter (DOM), which lose their EDC upon oxidation, but are partially transformed into quinones, which still absorb in the measured UV range. For higher specific ozone doses, the relative EDC abatement was lower than the relative UVA abatement, which can be explained by the oxidation of UV absorbing moieties (e.g. non-activated aromatic compounds), which contribute less to EDC. The abatement of the selected micropollutants (i.e., 17α-ethinylestradiol (EE2), carbamazepine (CBZ), atenolol (ATE), bezafibrate (BZF), ibuprofen (IBU), and p-chlorobenzoic acid (pCBA)) varied significantly depending on their reactivity with ozone in the examined specific ozone dose range of 0-1.45 mgO3/mgDOC. The decrease of EE2 and CBZ with high ozone reactivity was linearly proportional to the reduction of the relative residuals of UVA254 and EDC. The abatement of ATE, BZF, IBU, and pCBA with intermediate to low ozone reactivities was not significant in a first phase (UVA254/UVA254,0 = 1.00-0.70; EDC/EDC0 = 1.00-0.56) while their abatement was more efficient than the degradation of the relative residual UVA254 and much more noticeable than the degradation of the relative residual EDC in a second phase (UVA254/UVA254,0 = 0.70-0.25; EDC/EDC0 = 0.56-0.25) because the partially destroyed UV absorbing and electron donating DOM moieties become recalcitrant to ozone attack. Bromate formation was pronounced for specific ozone doses >0.25 mgO3/mgDOC. At these ozone doses, the residual DOM competes less with bromide for ozone as the electron-rich DOM moieties are almost completely degraded. Overall, these results imply that a combination of the relative residual UVA254 and EDC more truly reflects the intrinsic reactivity of DOM associated with the removal of micropollutants and bromate formation than the single use of the UV absorbance-based surrogate indicators.


The inflammatory footprints of alcohol-induced oxidative damage in neurovascular components.
Microvessels, the main components of the blood-brain barrier (BBB) are vulnerable to oxidative damage during alcohol-induced stress. Alcohol produces oxidative damage within the vessels and in the brain. Using our animal model of catheter implant into the common carotid artery (CCA), we trace the footprints of alcohol-induced oxidative damage and inflammatory process at the BBB and into the brain. The uniqueness of the finding is that ethanol causes oxidative damage in all neurovascular components by activating NADPH oxidase and inducible nitric oxide synthase in the brain. It is not the oxidants but the ethanol that traverses through the BBB because we found that the highly reactive peroxynitrite does not cross the BBB. Thus, oxidative damage is caused at the site of oxidant production in the microvessels and in the brain. Our data indicate that acetaldehyde (the primary metabolite of ethanol) is the inducer/activator of these enzymes that generate oxidants in brain neurovascular cells. Evidence for alcohol-induced BBB damage is indicated by the alterations of the tight junction protein occludin in intact microvessels. Importantly, we demonstrate that the site of BBB oxidative damage is also the site of immune cells aggregation in the microvessels, which paves the path for inflammatory footprints. These findings reveal the underlying mechanisms that ethanol-elicited BBB oxidative damage initiates the brain vascular inflammatory process, which ultimately leads to neuroinflammation.


Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns.
Despite the availability of national and international guidelines, evidence suggests that chronic obstructive pulmonary disease (COPD) treatment is not always prescribed according to recommendations. This study evaluated the current management of patients with COPD using a large UK primary-care database. This analysis used electronic patient records and patient-completed questionnaires from the Optimum Patient Care Research Database. Data on current management were analyzed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group and presence or absence of a concomitant asthma diagnosis, in patients with a COPD diagnosis at ≥35 years of age and with spirometry results supportive of the COPD diagnosis. A total of 24,957 patients were analyzed, of whom 13,557 (54.3%) had moderate airflow limitation (GOLD Stage 2 COPD). The proportion of patients not receiving pharmacologic treatment for COPD was 17.0% in the total COPD population and 17.7% in the GOLD Stage 2 subset. Approximately 50% of patients in both cohorts were receiving inhaled corticosteroids (ICS), either in combination with a long-acting β2-agonist (LABA; 26.7% for both cohorts) or a LABA and a long-acting muscarinic antagonist (LAMA; 23.2% and 19.9%, respectively). ICS + LABA and ICS + LABA + LAMA were the most frequently used treatments in GOLD Groups A and B. Of patients without concomitant asthma, 53.7% of the total COPD population and 50.2% of the GOLD Stage 2 subset were receiving ICS. Of patients with GOLD Stage 2 COPD and no exacerbations in the previous year, 49% were prescribed ICS. A high proportion of GOLD Stage 2 COPD patients were symptomatic on their current management (36.6% with modified Medical Research Council score ≥2; 76.4% with COPD Assessment Test score ≥10). COPD is not treated according to GOLD and National Institute for Health and Care Excellence recommendations in the UK primary-care setting. Some patients receive no treatment despite experiencing symptoms. Among those on treatment, most receive ICS irrespective of severity of airflow limitation, asthma diagnosis, and exacerbation history. Many patients on treatment continue to have symptoms.


Long-term effectiveness and safety of anti-TNF in pediatric-onset inflammatory bowel diseases: A population-based study.
Anti-TNF agents are the first biologic treatment option in inflammatory bowel disease (IBD). The long-term effectiveness of this strategy at the population level is poorly known, particularly in pediatric-onset IBD. All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011 in the EPIMAD population-based registry were followed retrospectively until 2013. Among patients treated with anti-TNF, the cumulative probabilities of anti-TNF failure defined by primary failure, loss of response (LOR) or intolerance were evaluated. Factors associated with anti-TNF failure were investigated by a Cox model. Among a total of 1,007 patients with CD and 337 patients with UC, respectively 481 (48%) and 81 (24%) were treated with anti-TNF. Median age at anti-TNF initiation was 17.4 years (IQR, 15.1-20.9). Median duration of anti-TNF therapy was 20.4 months (IQR, 6.0-59.9). In CD, the probability of failure of 1st line anti-TNF at 1, 3 and 5 years was respectively 30.7%, 51.3% and 61.9% for infliximab and 25.9%, 49.3% and 57.7% for adalimumab (p = 0.740). In UC, the probability of failure of 1st line anti-TNF therapy was respectively 38.4%, 52.3% and 72.7% for infliximab and 12.5% for these 3 timepoints for adalimumab (p = 0.091). The risk of failure was maximal in the first year of treatment and LOR was the main reason for discontinuation. Female gender was associated with LOR (HR, 1.48; 95%CI 1.02-2.14) and with anti-TNF withdrawal for intolerance in CD (HR, 2.31; 95%CI 1.30-4.11) and disease duration (≥ 2 y vs. < 2 y) was associated with LOR in UC (HR, 0.37; 95%CI 0.15-0.94) in multivariate analysis. Sixty-three (13.5%) patients observed adverse events leading to termination of treatment (p = 0.57). No death, cancer or tuberculosis was observed while the patients were under anti-TNF treatment. In a population-based study of pediatric-onset IBD, about 60% in CD and 70% in UC experienced anti-TNF failure within 5 years. Loss of response account for around two-thirds of failure, both for CD and UC.


Indefinite Proximity Learning: A Review.
Efficient learning of a data analysis task strongly depends on the data representation. Most methods rely on (symmetric) similarity or dissimilarity representations by means of metric inner products or distances, providing easy access to powerful mathematical formalisms like kernel or branch-and-bound approaches. Similarities and dissimilarities are, however, often naturally obtained by nonmetric proximity measures that cannot easily be handled by classical learning algorithms. Major efforts have been undertaken to provide approaches that can either directly be used for such data or to make standard methods available for these types of data. We provide a comprehensive survey for the field of learning with nonmetric proximities. First, we introduce the formalism used in nonmetric spaces and motivate specific treatments for nonmetric proximity data. Second, we provide a systematization of the various approaches. For each category of approaches, we provide a comparative discussion of the individual algorithms and address complexity issues and generalization properties. In a summarizing section, we provide a larger experimental study for the majority of the algorithms on standard data sets. We also address the problem of large-scale proximity learning, which is often overlooked in this context and of major importance to make the method relevant in practice. The algorithms we discuss are in general applicable for proximity-based clustering, one-class classification, classification, regression, and embedding approaches. In the experimental part, we focus on classification tasks.


[Falls and gait alterations in elderly].
There is a higher frequency of falls in the elderly than in young people, due to age related physiological changes in gait. There is a lower amplitude of pelvic movements that affects gait efficiency. Equilibrium is also disturbed since the trunk assumes the leadership of gait, displacing the pelvis. Many diseases of elderly individuals, such as Parkinson disease, spastic paraparesis, cerebrovascular accidents or neuropathies, further impair the gait. Therefore, after the age of 65, all falls must be considered symptomatic.


Multiple roles for executive control in belief-desire reasoning: distinct neural networks are recruited for self perspective inhibition and complexity of reasoning.
Belief-desire reasoning is a core component of 'Theory of Mind' (ToM), which can be used to explain and predict the behaviour of agents. Neuroimaging studies reliably identify a network of brain regions comprising a 'standard' network for ToM, including temporoparietal junction and medial prefrontal cortex. Whilst considerable experimental evidence suggests that executive control (EC) may support a functioning ToM, co-ordination of neural systems for ToM and EC is poorly understood. We report here use of a novel task in which psychologically relevant ToM parameters (true versus false belief; approach versus avoidance desire) were manipulated orthogonally. The valence of these parameters not only modulated brain activity in the 'standard' ToM network but also in EC regions. Varying the valence of both beliefs and desires recruits anterior cingulate cortex, suggesting a shared inhibitory component associated with negatively valenced mental state concepts. Varying the valence of beliefs additionally draws on ventrolateral prefrontal cortex, reflecting the need to inhibit self perspective. These data provide the first evidence that separate functional and neural systems for EC may be recruited in the service of different aspects of ToM.


Radiation Doses of Various CT Protocols: a Multicenter Longitudinal Observation Study.
Emerging concerns regarding the hazard from medical radiation including CT examinations has been suggested. The purpose of this study was to observe the longitudinal changes of CT radiation doses of various CT protocols and to estimate the long-term efforts of supervising radiologists to reduce medical radiation. Radiation dose data from 11 representative CT protocols were collected from 12 hospitals. Attending radiologists had collected CT radiation dose data in two time points, 2007 and 2010. They collected the volume CT dose index (CTDIvol) of each phase, number of phases, dose length product (DLP) of each phase, and types of scanned CT machines. From the collected data, total DLP and effective dose (ED) were calculated. CTDIvol, total DLP, and ED of 2007 and 2010 were compared according to CT protocols, CT machine type, and hospital. During the three years, CTDIvol had significantly decreased, except for dynamic CT of the liver. Total DLP and ED were significantly decreased in all 11 protocols. The decrement was more evident in newer CT scanners. However, there was substantial variability of changes of ED during the three years according to hospitals. Although there was variability according to protocols, machines, and hospital, CT radiation doses were decreased during the 3 years. This study showed the effects of decreased CT radiation dose by efforts of radiologists and medical society.


Radiometric Assessment of a UAV-Based Push-Broom Hyperspectral Camera.
The use of unmanned aerial vehicles (UAVs) for Earth and environmental sensing has increased significantly in recent years. This is particularly true for multi- and hyperspectral sensing, with a variety of both push-broom and snap-shot systems becoming available. However, information on their radiometric performance and stability over time is often lacking. The authors propose the use of a general protocol for sensor evaluation to characterize the data retrieval and radiometric performance of push-broom hyperspectral cameras, and illustrate the workflow with the Nano-Hyperspec (Headwall Photonics, Boston USA) sensor. The objectives of this analysis were to: (1) assess dark current and white reference consistency, both temporally and spatially; (2) evaluate spectral fidelity; and (3) determine the relationship between sensor-recorded radiance and spectroradiometer-derived reflectance. Both the laboratory-based dark current and white reference evaluations showed an insignificant increase over time (<2%) across spatial pixels and spectral bands for >99.5% of pixel-waveband combinations. Using a mercury/argon (Hg/Ar) lamp, the hyperspectral wavelength bands exhibited a slight shift of 1-3 nm against 29 Hg/Ar wavelength emission lines. The relationship between the Nano-Hyperspec radiance values and spectroradiometer-derived reflectance was found to be highly linear for all spectral bands. The developed protocol for assessing UAV-based radiometric performance of hyperspectral push-broom sensors showed that the Nano-Hyperspec data were both time-stable and spectrally sound.


Restraint stress enhances arterial thrombosis in vivo--role of the sympathetic nervous system.
Stress is known to correlate with the incidence of acute myocardial infarction. However, the molecular mechanisms underlying this correlation are not known. This study was designed to assess the effect of experimental stress on arterial thrombus formation, the key event in acute myocardial infarction. Mice exposed to 20 h of restraint stress displayed an increased arterial prothrombotic potential as assessed by photochemical injury-induced time to thrombotic occlusion. This increase was prevented by chemical sympathectomy performed through 6-hydroxydopamine (6-OHDA). Blood-born tissue factor (TF) activity was enhanced by stress and this increase could be prevented by 6-OHDA treatment. Vessel wall TF, platelet count, platelet aggregation, coagulation times (PT, aPTT), fibrinolytic system (t-PA and PAI-1) and tail bleeding time remained unaltered. Telemetric analysis revealed only minor hemodynamic changes throughout the stress protocol. Plasma catecholamines remained unaffected after restraint stress. Tumor necrosis factor alpha (TNF-α) plasma levels were unchanged and inhibition of TNF-α had no effect on stress-enhanced thrombosis. These results indicate that restraint stress enhances arterial thrombosis via the sympathetic nervous system. Blood-borne TF contributes, at least in part, to the observed effect whereas vessel wall TF, platelets, circulating coagulation factors, fibrinolysis and inflammation do not appear to play a role. These findings shed new light on the understanding of stress-induced cardiovascular events.


Consumers at the centre: interprofessional solutions for meeting mental health consumers' physical health needs.
Interprofessional care and consumer-oriented services are embodied in modern healthcare policy and practice. The views, needs, and values of consumers are essential to ensuring translation of policy to practice. This is particularly pertinent for people diagnosed with mental illness who experience a higher risk of physical health problems and premature death. A qualitative, exploratory research project was conducted, involving focus groups with members of a mental health consumer group in the Australian Capital Territory. Participants were asked about their experiences and opinions in relation to physical health and care and treatment provided. Focus group transcripts were thematically analysed. Three themes arose via analysis: (1) Meeting diverse physical healthcare needs, where mental health consumers connect with many types of healthcare providers, conventional and non-conventional, (2) centre of the interprofessional team for holistic care, where there is preference for a consumer-centred group effort in addressing health issues as the model of care, and (3) more gateways, less gatekeeping, where points of access were affected by cost, place and gatekeepers could be enabling. People with mental illness seek enhanced collaboration between a broader range of health professionals, with potential to contribute to their overall health and well-being.


Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis.
Stopping smoking is associated with many important improvements in health and quality of life. The use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease events associated within the quitting period. We aimed to examine whether the 3 licensed smoking cessation therapies-nicotine replacement therapy, bupropion, and varenicline-were associated with an increased risk of cardiovascular disease events using a network meta-analysis. We searched 10 electronic databases, were in communication with authors of published randomized, clinical trials (RCTs), and accessed internal US Food and Drug Administration reports. We included any RCT of the 3 treatments that reported cardiovascular disease outcomes. Among 63 eligible RCTs involving 21 nicotine replacement therapy RCTs, 28 bupropion RCTs, and 18 varenicline RCTs, we found no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54-1.73) or varenicline (RR, 1.30; 95% CI, 0.79-2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39-3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21-0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66-2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26-4.30). Smoking cessation therapies do not appear to raise the risk of serious cardiovascular disease events.


The importance of health co-benefits in macroeconomic assessments of UK Greenhouse Gas emission reduction strategies.
We employ a single-country dynamically-recursive Computable General Equilibrium model to make health-focussed macroeconomic assessments of three contingent UK Greenhouse Gas (GHG) mitigation strategies, designed to achieve 2030 emission targets as suggested by the UK Committee on Climate Change. In contrast to previous assessment studies, our main focus is on health co-benefits additional to those from reduced local air pollution. We employ a conservative cost-effectiveness methodology with a zero net cost threshold. Our urban transport strategy (with cleaner vehicles and increased active travel) brings important health co-benefits and is likely to be strongly cost-effective; our food and agriculture strategy (based on abatement technologies and reduction in livestock production) brings worthwhile health co-benefits, but is unlikely to eliminate net costs unless new technological measures are included; our household energy efficiency strategy is likely to breakeven only over the long term after the investment programme has ceased (beyond our 20 year time horizon). We conclude that UK policy makers will, most likely, have to adopt elements which involve initial net societal costs in order to achieve future emission targets and longer-term benefits from GHG reduction. Cost-effectiveness of GHG strategies is likely to require technological mitigation interventions and/or demand-constraining interventions with important health co-benefits and other efficiency-enhancing policies that promote internalization of externalities. Health co-benefits can play a crucial role in bringing down net costs, but our results also suggest the need for adopting holistic assessment methodologies which give proper consideration to welfare-improving health co-benefits with potentially negative economic repercussions (such as increased longevity).


Pseudomonas aeruginosa manipulates redox and iron homeostasis of its microbiota partner Aspergillus fumigatus via phenazines.
The opportunistic fungal pathogen Aspergillus fumigatus is increasingly found as a coinfecting agent along with Pseudomonas aeruginosa in cystic fibrosis patients. Amongst the numerous molecules secreted by P. aeruginosa during its growth, phenazines constitute a major class. P. aeruginosa usually secreted four phenazines, pyocyanin (PYO), phenazine-1-carboxamide (PCN), 1-hydroxyphenazine (1-HP) and phenazine-1-carboxylic acid (PCA). These phenazines inhibited the growth of A. fumigatus but the underlying mechanisms and the impact of these four phenazines on A. fumigatus biology were not known. In the present study, we analyzed the functions of the four phenazines and their mode of action on A. fumigatus. All four phenazines showed A. fumigatus growth inhibitory effects by inducing production of reactive oxygen species (ROS), specifically O2(·-), and reactive nitrogen species (RNS), ONOO(-). A. fumigatus Sod2p was the major factor involved in resistance against the ROS and RNS induced by phenazines. Sub-inhibitory concentrations of PYO, PCA and PCN promote A. fumigatus growth by an independent iron-uptake acquisition. Of the four phenazines 1-HP had a redox-independent function; being able to chelate metal ions 1-HP induced A. fumigatus iron starvation. Our data show the fine-interactions existing between A. fumigatus and P. aeruginosa, which can lead to stimulatory or antagonistic effects.


T cell receptor antagonism interferes with MHC clustering and integrin patterning during immunological synapse formation.
T cell activation by nonself peptide-major histocompatibility complex (MHC) antigenic complexes can be blocked by particular sequence variants in a process termed T cell receptor antagonism. The inhibition mechanism is not understood, although such variants are encountered in viral infections and may aid immune evasion. Here, we study the effect of antagonist peptides on immunological synapse formation by T cells. This cellular communication process features early integrin engagement and T cell motility arrest, referred to as the "stop signal." We find that synapses formed on membranes presenting antagonist-agonist complexes display reduced MHC density, which leads to reduced T cell proliferation that is not overcome by the costimulatory ligands CD48 and B7-1. Most T cells fail to arrest and crawl slowly with a dense ICAM-1 crescent at the leading edge. Similar aberrant patterns of LFA-1/ICAM-1 engagement in live T-B couples correlate with reduced calcium flux and IL-2 secretion. Hence, antagonist peptides selectively disable MHC clustering and the stop signal, whereas LFA-1 valency up-regulation occurs normally.


Range expansion through fragmented landscapes under a variable climate.
Ecological responses to climate change may depend on complex patterns of variability in weather and local microclimate that overlay global increases in mean temperature. Here, we show that high-resolution temporal and spatial variability in temperature drives the dynamics of range expansion for an exemplar species, the butterfly Hesperia comma. Using fine-resolution (5 m) models of vegetation surface microclimate, we estimate the thermal suitability of 906 habitat patches at the species' range margin for 27 years. Population and metapopulation models that incorporate this dynamic microclimate surface improve predictions of observed annual changes to population density and patch occupancy dynamics during the species' range expansion from 1982 to 2009. Our findings reveal how fine-scale, short-term environmental variability drives rates and patterns of range expansion through spatially localised, intermittent episodes of expansion and contraction. Incorporating dynamic microclimates can thus improve models of species range shifts at spatial and temporal scales relevant to conservation interventions.


Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease.
The beta-site of beta-amyloid precursor protein cleaving enzyme (BACE) cleaves the beta-amyloid (Abeta) precursor protein at the N-terminal end of Abeta, allowing for the production of Abeta by C-terminal gamma-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Abeta, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.


Extending the RIGHT statement for reporting adapted practice guidelines in healthcare: the RIGHT-Ad@pt Checklist protocol.
The adaptation of guidelines is an increasingly used methodology for the efficient development of contextualised recommendations. Nevertheless, there is no specific reporting guidance. The essential Reporting Items of Practice Guidelines in Healthcare (RIGHT) statement could be useful for reporting adapted guidelines, but it does not address all the important aspects of the adaptation process. The objective of our project is to develop an extension of the RIGHT statement for the reporting of adapted guidelines (RIGHT-Ad@pt Checklist). To develop the RIGHT-Ad@pt Checklist, we will use a multistep process that includes: (1) establishment of a Working Group; (2) generation of an initial checklist based on the RIGHT statement; (3) optimisation of the checklist (an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review by guideline developers and users and a final assessment of adapted guidelines); and (4) approval of the final checklist. At each step of the process, we will calculate absolute frequencies and proportions, use content analysis to summarise and draw conclusions, discuss the results, draft a report and refine the checklist. We have obtained a waiver of approval from the Clinical Research Ethics Committee at the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain). We will disseminate the RIGHT-Ad@pt Checklist by publishing into a peer-reviewed journal, presenting to relevant stakeholders and translating into different languages. We will continuously seek feedback from stakeholders, surveil new relevant evidence and, if necessary, update the checklist.


Hepatitis B surface antigen disappearance and hepatitis B surface antigen subtype: a prospective, long-term, follow-up study of Japanese residents of Okinawa, Japan with chronic hepatitis B virus infection.
To determine the natural course of hepatitis B surface antigen (HBsAg) disappearance in chronic hepatitis B virus (HBV) infection and the factors related to its disappearance, 946 HBsAg carriers in Okinawa, Japan were prospectively followed for up to 19 years (mean = 9.2 years). The disappearance of HBsAg, as determined by radioimmunoassay (RIA), was observed in 62 (6.6%) and the overall annual disappearance rate was 0.79%/year. Its disappearance was more frequent in 60 (7.4%) of 815 serum samples negative for hepatitis B e antigen (HBeAg) by RIA at entry compared with only two (1.5%) of 131 serum samples that were HBeAg positive by RIA at entry (P < 0.05). Stepwise logistic regression analysis showed that age and HBsAg subtype were significantly associated with HBsAg disappearance (both P < 0.05), and that carriers with subtype adr (odds ratio = 2.87) had an increased probability of clearing HBsAg compared with carriers with subtype adw. Conversely, HBeAg disappearance was earlier in those with the adw subtype than in those with adr. Hepatitis B virus DNA was not detected by the polymerase chain reaction after HBsAg disappearance in any of the 62 from whom it had disappeared. The HBsAg titer, as measured by reverse passive hemagglutination, was related to the time to its disappearance; the higher the titer, the longer the time to disappearance. These findings suggest that HBeAg negativity, a more advanced age, and low titers of HBsAg are favorable factors for HBsAg disappearance in the natural course of chronic HBV infection. Moreover, HBsAg subtype adr was a predictive factor for HBsAg disappearance, whereas subtype adw was predictive of early HBeAg disappearance.


Pediatric glossopharyngeal neuralgia: a comprehensive review.
Debilitating facial pain can seriously affect an individual's daily living. Given that the pathophysiology behind neuropathic and myofascial pain is not fully understood, when chronic facial pain goes undiagnosed, it has been proposed that one of the two is the likely cause. Since their discovery, glossopharyngeal neuralgia (GN) and Eagle's syndrome have been considered mostly conditions afflicting the adult population. However, when pediatric patients present with symptoms resembling GN or Eagle's syndrome, physicians are less apt to include these as a differential diagnosis simply due to the low prevalence and incidence in the pediatric population. A literature review was performed with the aim to better understand the history of reported cases and to provide a comprehensive report of the anatomical variations that lead to these two conditions as well as the way these variations dictated medical and surgical management. Articles were obtained through Google Scholar and PubMed. Search criteria included key phrases such as pediatric glossopharyngeal neuralgia and pediatric Eagle syndrome. These key phrases were searched independently. PubMed was searched primarily then cross-referenced articles were found via Google Scholar. Results from non-English articles were excluded. A total of 58 articles were reviewed. Most of the articles focused on adult glossopharyngeal neuralgia, and the majority was comprised of case reports. When searched via PubMed, a total of 16 articles and 2 articles returned for glossopharyngeal neuralgia and Eagle's syndrome, respectively. After criteria selection and cross-referencing, a total of seven articles were found with respect to pediatric glossopharyngeal neuralgia. While they are rare conditions, there are multiple etiologies that lead to the debilitating symptoms of GN and Eagle's syndrome. The clinical anatomy proved notable as multiple causes of GN and Eagle's syndrome are due to variation in the anatomy of the neurovascular structures surrounding the glossopharyngeal nerve, an elongated styloid process, a calcified stylohyoid ligament as well as a calcified stylomandibular ligament. Due to the success of different treatment modalities, the treatment of choice is dependent on clinical judgment.


Fiber-based free-space optical coherent receiver with vibration compensation mechanism.
We propose a novel fiber-based free-space optical (FSO) coherent receiver for inter-satellite communication. The receiver takes advantage of established fiber-optic components and utilizes the fine-pointing subsystem installed in FSO terminals to minimize the influence of satellite platform vibrations. The received beam is coupled to a single-mode fiber, and the coupling efficiency of the system is investigated both analytically and experimentally. A receiving sensitivity of -38 dBm is obtained at the forward error correction limit with a transmission rate of 22.4 Gbit/s. The proposed receiver is shown to be a promising component for inter-satellite optical communication.


Modulation of untruthful responses with non-invasive brain stimulation.
Deceptive abilities have long been studied in relation to personality traits. More recently, studies explored the neural substrates associated with deceptive skills suggesting a critical role of the prefrontal cortex. Here we investigated whether non-invasive brain stimulation over the dorsolateral prefrontal cortex (DLPFC) could modulate generation of untruthful responses about subject's personal life across contexts (i.e., deceiving on guilt-free questions on daily activities; generating previously memorized lies about past experience; and producing spontaneous lies about past experience), as well as across modality responses (verbal and motor responses). Results reveal that real, but not sham, transcranial direct current stimulation (tDCS) over the DLPFC can reduce response latency for untruthful over truthful answers across contexts and modality responses. Also, contexts of lies seem to incur a different hemispheric laterality. These findings add up to previous studies demonstrating that it is possible to modulate some processes involved in generation of untruthful answers by applying non-invasive brain stimulation over the DLPFC and extend these findings by showing a differential hemispheric contribution of DLPFCs according to contexts.


Animal origins of SARS coronavirus: possible links with the international trade in small carnivores.
The search for animal host origins of severe acute respiratory syndrome (SARS) coronavirus has so far remained focused on wildlife markets, restaurants and farms within China. A significant proportion of this wildlife enters China through an expanding regional network of illegal, international wildlife trade. We present the case for extending the search for ancestral coronaviruses and their hosts across international borders into countries such as Vietnam and Lao People's Democratic Republic, where the same guilds of species are found on sale in similar wildlife markets or food outlets. The three species that have so far been implicated, a viverrid, a mustelid and a canid, are part of a large suite of small carnivores distributed across this region currently overexploited by this international wildlife trade. A major lesson from SARS is that the underlying roots of newly emergent zoonotic diseases may lie in the parallel biodiversity crisis of massive species loss as a result of overexploitation of wild animal populations and the destruction of their natural habitats by increasing human populations. To address these dual threats to the long-term future of biodiversity, including man, requires a less anthropocentric and more interdisciplinary approach to problems that require the combined research expertise of ecologists, conservation biologists, veterinarians, epidemiologists, virologists, as well as human health professionals.


Differential diagnosis of gastrointestinal stromal tumor by histopathology and immunohistochemistry.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract. GISTs account for approximately 80% of the clinically relevant GI mesenchymal tumors. Although most GISTs show spindle cell morphology, 10-15% of GISTs show pure epithelioid configuration. Therefore, not only spindle cell tumors but also epithelioid cell ones developing in the GI tract are subject to the differential diagnoses of GISTs. GISTs are basically positive for KIT, a receptor tyrosine kinase (RTK) encoded by protooncogene c-kit, by immunohistochemistry, but approximately 5% of GISTs are only weakly or barely positive for KIT. Since almost all spindle cell type GISTs are strongly and diffusely positive for KIT regardless of different genetic subtypes, diagnosis of the spindle cell type GISTs is not difficult. On the other hand, epithelioid cell type GISTs show different staining patterns of KIT in different genetic backgrounds. Approximately half of the epithelioid cell type GISTs with platelet-derived growth factor receptor alpha (PDGFRA) gene mutation might show weak or undetectable staining of KIT. On the other hand, almost all GISTs are negative for desmin, which is a positive marker for mature smooth muscle cells, and S100 protein, which is a Schwann cell marker. Smooth muscle tumors such as leiomyomas and leiomyosarcomas, which usually show the spindle cell morphology, consist of approximately 10% of the clinically relevant GI mesenchymal tumors and are almost positive for desmin and negative for KIT and S100 protein. Schwannomas which nearly always show the spindle cell pattern, comprise up to 5% of the GI mesenchymal tumors, and almost all of them are positive for S100 protein and negative for KIT and desmin. Thus, most GI mesenchymal tumors are differentially diagnosed by immunohistochemistry (IHC) of KIT, desmin and S100 protein. However, mesenchymal tumors such as desmoids, solitary fibrous tumors (SFTs), inflammatory myofibroblastic tumors (IMTs), perivascular epithelioid cell tumors (PEComas), inflammatory fibroid polyps (IFPs), rarely develop in the GI tract, and have to be correctly diagnosed through detection of specific immunohistochemical markers and/or unique genetic aberrations.


[The prevalence of and factors associated with depression in Colombia].
To analyze the prevalence of depression and the factors associated with it in Colombia in 2000 and 2001. For this descriptive cross-sectional study a survey was conducted between November 2000 and January 2001 with 1,116 men and women 18 years of age or older who were living in private homes that were selected through a multistage national representative sampling, stratified according to the degree of urbanization of the area included in the sampling. Depression was classified as brief recurrent depression, subclinical depression, or mild, moderate, or serious clinical depressive episodes in the 30 days and in the 12 months prior to the interview. Simple and stratified frequencies of over 500 variables, along with their 95% confidence intervals (95% CIs), were calculated by age and gender. The association that the selected variables had with depressive episodes was evaluated through a multivariate logistic regression model. Of the persons studied, 10.0% of them (95% CI: 9.2% to 10.7%) had had a depressive episode in the 12 months prior to the survey, and 8.5% (95% CI: 7.8% to 9.2%) had suffered a depressive episode in the preceding month. There was a higher proportion of women with depression in both of the periods. More than 50% of the episodes were moderate, in both men and women. There were higher prevalences of depression in persons older than 45 years. The factors associated with depression in the preceding month were: female gender; considering one's health to be moderate or bad; suffering from pain or discomfort; having difficulties in interpersonal relations; consuming marijuana, addictive substances, stimulants, or tranquilizers; being dependent on alcohol; and being unemployed and unable to work. Depression is a frequent disorder in Colombia. Measures directed at reducing the risk of depression should be implemented, especially among women and in persons over 45 years old.


Inhibition of sphingosine-1-phosphate phosphatase 1 promotes cancer cells migration in gastric cancer: Clinical implications.
Sphingosine-1-phosphate (S1P) plays an important role in regulating many biological processes. Sphingosine-1-phosphate phosphatase 1 (SGPP1) can dephosphorylate S1P into sphingosine and tip the balance of sphingosine-S1P. Increased levels of sphingosine leads to a decrease in the ability of cell invasion as well as an increase in the ability of cell apoptosis. However, little is known regarding the effects of SGPP1 in gastric cancer. The present study examined the function of SGPP1 on gastric cancer cell lines as well as its clinical relevance in gastric cancer progression. Using immunohistochemistry and RT-qPCR techniques, the clinical significance of SGPP1 expression was analyzed in 288 paraffin-embedded gastric tissue specimens and 219 fresh gastric tissues, respectively. Transgenes encoding ribozymes to specifically target human SGPP1 (pEF-SGPP1) was constructed. Human gastric cancer cell lines (AGS and HGC27) were transfected with pEF-SGPP1 transgene and examined by functional analysis. SGPP1 was downregulated in gastric cancer tissues, compared with adjacent normal gastric tissues (p=0.034). SGPP1 mRNA levels in gastric cancer tissues were significantly decreased when compared with their adjacent non-cancerous tissues (p<0.001). Weakly expressed SGPP1 was positively correlated with the lymph node metastasis (p=0.005) and distant metastasis (p=0.031). Kaplan-Meier survival curves revealed that patients with SGPP1 positive expression had a significant increase in overall survival (OS) (p=0.034) and progression-free survival (PFS) (p=0.041). Multivariate analysis indicated the expression of SGPP1 was an independent prognostic factor in gastric cancer patients (p=0.041). In vitro experiments showed that knockdown of SGPP1 resulted in an increase in the invasion (2-fold) and migration (5-fold) of AGS and HGC27. The two gastric cancer cells transfected with pEF-SGPP1 exhibited a slower rate of growth with less adhesion. Thus, our findings provided evidence that SGPP1 may serve as a prognostic biomarker for patients with advanced gastric cancers.


Post synthetic exchange enables orthogonal click chemistry in a metal organic framework.
Biphenyl-4,4'-dicarboxylic acid derivatives containing either azide or acetylene functional groups were inserted into UiO-67 metal organic frameworks (MOFs) via post synthetic linker exchange. Sequential and orthogonal click reactions could be performed on these modified MOFs by incubating the crystals with small molecule substrates bearing azide or acetylene groups in the presence of a copper catalyst. 1H NMR of digested MOF samples showed that up to 50% of the incorporated linkers could be converted to their "clicked" triazole products. Powder X-ray diffraction confirmed that the UiO-67 structure was maintained throughout all transformations. The click reaction efficiency is discussed in context of MOF crystallite size and pore size. As the incorporation of clicked linkers could be controlled by post synthetic exchange, this work introduces a powerful method of quickly introducing orthogonal modifications into known MOF architectures.


A systematic review of the femoral origin and tibial insertion morphology of the ACL.
Transtibial single bundle anterior cruciate ligament (ACL) reconstruction has been the gold standard for several years. This technique often fails to restore native ACL femoral origin and tibial insertion anatomy of the ACL. Recently, there is a strong trend towards a more anatomical approach in single and double bundle ACL reconstruction. Using the anatomic double bundle structure of the ACL as a principle, the entirety of both tibial insertion and femoral origin of both bundles, the posterolateral and anteromedial, may be restored. Reflected by recent publications over the past two years, there is an increasing interest in the anatomy of the ACL. In the current study, a PubMed literature search was performed looking for measurements of the ACL femoral origin and tibial insertion. These studies show a large variability in the size and the anatomy of the femoral origin and tibial ACL insertion using different methods and specimens. The diversity of reported measurements makes clinical application of these data difficult at best. Thus, it is of paramount importance to understand the individual variations in size and shape of the ACL femoral origin and tibial ACL insertion. This study is a systematic review of the morphology of the ACL femoral origin and tibial insertion as reported in the literature.


Techniques and materials for skin closure in caesarean section.
Caesarean section is a common operation with no agreed standard on operative techniques and materials to use. The skin layer can be repaired by sub cuticular stitch immediately below the skin layer, an interrupted stitch or with skin staples. A great variety of materials and techniques are used for skin closure after caesarean section and there is a need to identify which provide the best outcomes for women. To compare the effects of skin closure techniques and materials on maternal outcomes and time taken to perform a caesarean section. We searched the Cochrane Pregnancy and Childbirth Group trials register (August 2002). All randomised comparisons of skin closure techniques in caesarean section. Three papers were identified from the search. Data were extracted independently by two reviewers. On further inspection two were not considered to be randomised controlled trials. Only one small randomised controlled trial, involving 66 women, was included in the review. Frishman et al compared staples with absorbable sub-cuticular suture for closure following caesarean section. While operating time was significantly shorter when using staples, the use of absorbable sub cuticular suture resulted in less postoperative pain and yielded a better cosmetic result at the post-operative visit. There is no conclusive evidence about how the skin should be closed after caesarean section. Questions regarding the best closure technique and material and the outcomes associated with each remain unanswered. The appearance and strength of the scar following caesarean section is important to women and the choice of technique and materials should be made by women in consultation with their obstetrician based on the limited information currently available.


The safety of infliximab infusions in the community setting.
Tumour necrosis factor-alpha (TNFalpha) has an important role in the pathogenesis of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, ulcerative colitis and psoriasis. Infliximab, a chimeric anti-TNFalpha monoclonal antibody, has been shown to reduce the severity of symptoms or induces remission of active disease. Infusions have generally been limited to the hospital setting due to cost and concerns for patient safety. Studies defining its efficacy and safety have, therefore, originated almost exclusively from hospital settings. To evaluate the safety of infliximab in a community clinic environment, across all types of patients. A retrospective chart review of 3161 patients who received a combined 20,976 infusions at a network of community clinics over 16.5 months was conducted. Adverse drug reaction (ADR) information was retrieved and coded for time of onset, severity and outcome. Only ADRs that occurred during or within the first 24 h of the infusion were included. A total of 524 (2.5% of all infusions) acute ADRs in 353 patients (11.2%) were recorded. Most reactions (ie, ADRs) were mild (n=263 [50.2%, 1.3% of all infusions]) or moderate (n=233 [44.5%, 1.1% of all infusions]). Twenty-eight reactions (5.3%, 0.1% of all infusions) were severe. Emergency medical services were called to transport patients to hospital for seven of the severe reactions, of which none required admission. As per pre-established medical directives, adrenaline was administered three times. Infliximab infusions are safe in the community setting. Severe ADRs were rare. None required active physician intervention; nurses were able to treat all reactions by following standardized medical directives.


Environmental factor and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis.
Autoimmune diseases are initiated by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. Autoantibody production and an imbalance of effector and regulatory T-cells are hallmarks of autoimmune dysregulation. While expansion of circulating effector memory T-cells is linked to disease pathogenesis and progression, the causes driving alterations of the peripheral T-cell compartment have remained poorly understood so far. In granulomatosis with polyangiitis (GPA), a prototypical autoimmune disorder of unknown aetiology, we performed for the first time a combined approach using phenotyping, transcriptome and functional analyses of T-cell populations to evaluate triggers of memory T-cell expansion. In more detail, we found increased percentages of circulating CD4+CD28-, CD8+CD28- and CD4+CD161+ single-positive and CD4+CD8+ double-positive T-cells in GPA. Transcriptomic profiling of sorted T-cell populations showed major differences between GPA and healthy controls reflecting antigen- (bacteria, viruses, fungi) and cytokine-driven impact on T-cell populations in GPA. Concomitant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) - positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA-patients compared to sole CMV- or EBV-positivity or CMV- and EBV-negativity. T-cells specific for other viruses (influenza A virus, metapneumovirus, respiratory syncytial virus) and the autoantigen proteinase 3 (PR3) were infrequently detected in GPA. Antigen-specific T-cells were not specifically enriched in any of the T-cell subsets. Altogether, on a genetic and cellular basis, here we show that alterations of the peripheral T-cell compartment are driven by inflammation and various environmental factors including concomitant CMV and EBV infection. Our study provides novel insights into mechanisms driving autoimmune disease and on potential therapeutic targets.


Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis.
Mycophenolate mofetil (MMF) is an immune suppressive initially introduced for the prevention of solid organ allograft rejection that is increasingly used in autoimmune conditions, including vasculitis. This retrospective study evaluated the efficacy and tolerability of MMF in 51 sequential patients with anti-neutrophil cytoplasm antibodies-associated systemic vasculitis (AASV) treated in a single centre between 2001 and 2004. The mean age was 54 years and median disease duration was 36 months. A mean of 3.5 systems were involved and the previous median exposure to cyclophosphamide was 9 g. MMF was administered either as remission maintenance therapy (29/51, 56.9%) or as treatment for active disease (22/51, 43.1%). The mean duration of MMF therapy was 20 months and the mean MMF dose during the first year was 1.6 g/day. 14/29 (48.3%) of those receiving MMF for remission maintenance therapy eventually relapsed with a mean time to relapse of 14 months. Of those receiving MMF for relapsing disease, 3 failed to respond to therapy while the rest achieved remission by 3.9 months. However, 9 of these subsequently flared; mean time to disease flare was also 14 months. MMF was withdrawn in 28 patients (54.9%) because of treatment inefficacy in 21, severe adverse events in 5 and intolerance in 2. Of the 51 treated, 36 (70.6%) experienced at least 1 side effect, namely infections in 24, gastrointestinal side effects in 12 and psychological events in 6 patients. We have observed varying efficacy of MMF in AASV, with over 50% of patients with relapsing disease achieving remission and marked falls in concomitant steroid doses. However, longer follow-up indicates a subsequent relapse rate of over 50% that may be associated with low MMF dosing.


Musculocutaneous neuropathy: case report and discussion.
The musculocutaneous nerve arises from the lateral cord of the brachial plexus and contains fibers from the C5, C6, and C7 spinal nerve roots. It innervates such muscles as the biceps brachii and brachialis as well as supply branches to the skin over the lateral cubital and forearm regions via the lateral antebrachial cutaneous nerve. Musculocutaneous neuropathy can arise from exercise, participating in sports, strenuous activity, cast placement, trauma, and surgery in addition to other less understood causes such as Parsonage Turner syndrome. We present the case of a 55-year-old female who complained of numbness, weakness, and pain throughout the arm starting 1 day following a surgical procedure. Electrodiagnostic testing revealed a musculocutaneous neuropathy with significant axonal injury. Symptoms of musculocutaneous neuropathy may be similar to cervical spinal nerve root impingement or brachial plexus lesions. Therefore, magnetic resonance imaging and electrodiagnostic studies may be useful in differentiating between these conditions. Once the diagnosis of musculocutaneous neuropathy has been made, treatments include relative rest, nonsteroidal anti-inflammatory drugs, splinting, physical therapy, and surgical decompression in cases that do not respond to conservative management.


Djinn Lite: a tool for customised gene transcript modelling, annotation-data enrichment and exploration.
There is an ever increasing rate of data made available on genetic variation, transcriptomes and proteomes. Similarly, a growing variety of bioinformatic programs are becoming available from many diverse sources, designed to identify a myriad of sequence patterns considered to have potential biological importance within inter-genic regions, genes, transcripts, and proteins. However, biologists require easy to use, uncomplicated tools to integrate this information, visualise and print gene annotations. Integrating this information usually requires considerable informatics skills, and comprehensive knowledge of the data format to make full use of this information. Tools are needed to explore gene model variants by allowing users the ability to create alternative transcript models using novel combinations of exons not necessarily represented in current database deposits of mRNA/cDNA sequences. Djinn Lite is designed to be an intuitive program for storing and visually exploring of custom annotations relating to a eukaryotic gene sequence and its modelled gene products. In particular, it is helpful in developing hypothesis regarding alternate splicing of transcripts by allowing the construction of model transcripts and inspection of their resulting translations. It facilitates the ability to view a gene and its gene products in one synchronised graphical view, allowing one to drill down into sequence related data. Colour highlighting of selected sequences and added annotations further supports exploration, visualisation of sequence regions and motifs known or predicted to be biologically significant. Gene annotating remains an ongoing and challenging task that will continue as gene structures, gene transcription repertoires, disease loci, protein products and their interactions become more precisely defined. Djinn Lite offers an accessible interface to help accumulate, enrich, and individualize sequence annotations relating to a gene, its transcripts and translations. The mechanism of transcript definition and creation, and subsequent navigation and exploration of features, are very intuitive and demand only a short learning curve. Ultimately, Djinn Lite can form the basis for providing valuable clues to plan new experiments, providing storage of sequences and annotations for dedication to customised projects. The application is appropriate for Windows 98-ME-2000-XP-2003 operating systems.


BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy.
Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis' Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.


DNA inversion in the tail fiber gene alters the host range specificity of carotovoricin Er, a phage-tail-like bacteriocin of phytopathogenic Erwinia carotovora subsp. carotovora Er.
Carotovoricin Er is a phage-tail-like bacteriocin produced by Erwinia carotovora subsp. carotovora strain Er, a causative agent for soft rot disease in plants. Here we studied binding and killing spectra of carotovoricin Er preparations for various strains of the bacterium (strains 645Ar, EC-2, N786, and P7) and found that the preparations contain two types of carotovoricin Er with different host specificities; carotovoricin Era possessing a tail fiber protein of 68 kDa killed strains 645Ar and EC-2, while carotovoricin Erb with a tail fiber protein of 76 kDa killed strains N786 and P7. The tail fiber proteins of 68 and 76 kDa had identical N-terminal amino acid sequences for at least 11 residues. A search of the carotovoricin Er region in the chromosome of strain Er indicated the occurrence of a DNA inversion system for the tail fiber protein consisting of (i) two 26-bp inverted repeats inside and downstream of the tail fiber gene that flank a 790-bp fragment and (ii) a putative DNA invertase gene with a 90-bp recombinational enhancer sequence. In fact, when a 1,400-bp region containing the 790-bp fragment was amplified by a PCR using the chromosomal DNA of strain Er as the template, both the forward and the reverse nucleotide sequences of the 790-bp fragment were detected. DNA inversion of the 790-bp fragment also occurred in Escherichia coli DH5alpha when two compatible plasmids carrying either the 790-bp fragment or the invertase gene were cotransformed into the bacterium. Furthermore, hybrid carotovoricin CGE possessing the tail fiber protein of 68 or 76 kDa exhibited a host range specificity corresponding to that of carotovoricin Era or Erb, respectively. Thus, a DNA inversion altered the C-terminal part of the tail fiber protein of carotovoricin Er, altering the host range specificity of the bacteriocin.


Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411.
The primary objective of this study was to assess the 1-year survival of patients with locally advanced, unresectable pancreatic cancer treated with the combination of bevacizumab, capecitabine, and radiation. Secondary end points were toxicity, progression-free survival (PFS), and response rate (RR). Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m(2) orally twice daily on days of radiation and bevacizumab 5 mg/kg on days 1, 15, and 29 followed by maintenance gemcitabine 1 g/m(2) weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks, both in 4-week cycles until progression. Treatment plans were reviewed for quality assurance (QA). Between January 2005 and February 2006, 82 eligible patients were treated. The median and 1-year survival rates were 11.9 months (95% CI, 9.9 to 14.0 months) and 47% (95% CI, 36% to 57%). Median PFS was 8.6 months (95% CI, 6.9 to 10.5), and RR was 26%. Overall, 35.4% of patients had grade 3 or greater treatment-related gastrointestinal toxicity (22.0% during chemoradiotherapy, 13.4% during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (ie, inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45% v 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; P = .05). The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine resulted in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer. Prospective QA may help limit toxicity in future trials.


The effects of question repetition on responses when prosecutors and defense attorneys question children alleging sexual abuse in court.
This study examined the effects of repeated questions (n = 12,169) on 6- to 12-year-olds' testimony in child sexual abuse cases. We examined transcripts of direct- and cross-examinations of 120 children, categorizing how attorneys asked repeated questions in-court and how children responded. Defense attorneys repeated more questions (33.6% of total questions asked) than prosecutors (17.8%) and repeated questions using more suggestive prompts (38% of their repeated questions) than prosecutors (15%). In response, children typically repeated or elaborated on their answers and seldom contradicted themselves. Self-contradictions were most often elicited by suggestive and option-posing prompts posed by either type of attorney. Child age did not affect the numbers of questions repeated, the types of prompts used by attorneys to repeat questions, or how children responded to repetition. Most (61.5%) repeated questions were repeated more than once and, as repetition frequency increased, so did the number of self-contradictions. "Asked-and-answered" objections were rarely raised (n = 45) and were more likely to be overruled than sustained by judges. Findings suggest that attorneys frequently ask children "risky" repeated questions. Both attorneys and the judiciary need more training in identifying and restricting the unnecessary repetition of questions.


A Scoping Review of Inclusive Out-of-School Time Physical Activity Programs for Children and Youth With Physical Disabilities.
The objective of this study was to comprehensively evaluate inclusive out-of-school time physical activity programs for children/youth with physical disabilities. A search of the published literature was conducted and augmented by international expertise. A quality appraisal was conducted; only studies with quality ratings ≥60% informed our best practice recommendations. Seventeen studies were included using qualitative (n = 9), quantitative (n = 5), or mixed (n = 3) designs. Programs had a diversity of age groups, group sizes, and durations. Most programs were recreational level, involving both genders. Rehabilitation staff were the most common leaders. Outcomes focused on social skills/relationships, physical skill development, and psychological well-being, with overall positive effects shown in these areas. The best practice recommendations are consistent with an abilities-based approach emphasizing common group goals and interests; cooperative activities; mastery-oriented, individualized instruction; and developmentally appropriate, challenging activities. Results indicate that inclusive out-of-school time physical activity programs are important for positive psychosocial and physical skill development of children/youth with physical disabilities.


How Medicare's payment cuts for cancer chemotherapy drugs changed patterns of treatment.
The Medicare Prescription Drug, Improvement, and Modernization Act, enacted in 2003, substantially reduced payment rates for chemotherapy drugs administered on an outpatient basis starting in January 2005. We assessed how these reductions affected the likelihood and setting of chemotherapy treatment for Medicare beneficiaries with newly diagnosed lung cancer, as well as the types of agents they received. Contrary to concerns about access, we found that the changes actually increased the likelihood that lung cancer patients received chemotherapy. The type of chemotherapy agents administered also changed. Physicians switched from dispensing the drugs that experienced the largest cuts in profitability, carboplatin and paclitaxel, to other high-margin drugs, like docetaxel. We do not know what the effect was on cancer patients, but these changes may have offset some of the savings projected from passage of the legislation. The ultimate message is that payment reforms have real consequences and should be undertaken with caution.


Urokinase plasminogen activator receptor, beta 2-integrins, and Src-kinases within a single receptor complex of human monocytes.
The glycosylphosphatidylinositol (GPI)-anchored membrane protein urokinase plasminogen activator-receptor (uPA-R; CD87) is one of the key molecules involved in migration of leukocytes and tumor cells. uPA bound to uPA-R provides the cell proteolytic potential used for degradation of extracellular matrix. uPA-R is also involved in induction of cell adhesion and chemotaxis. Here, we provide a molecular explanation for these uPA-R-related cellular events. By size fractionation of monocyte lysate and affinity isolation on its natural ligand uPA, we demonstrate uPA-R as a component of a receptor complex of relatively large size. Reprecipitation and immunoblotting techniques allowed us to detect the protein tyrosine kinases (PTKs) p60fyn, p53/56lyn, p58/64hck, and p59fgr as components of this "uPA-R complex". Activation of monocytes even with enzymatically inactivated uPA resulted in induction of tyrosine phosphorylation, suggesting modulation of uPA-R-associated PTKs upon ligand binding. In spite of their presence in large complexes, we did not find the GPI-linked proteins CD14, CD58, and CD59 in the uPA-R complex, which indicates the presence of different receptor domains containing GPI-linked proteins in monocytes. However, we identified the leukocyte integrins LFA-1 and CR3 as components of the uPA-R complex as indicated by coisolation of these molecules, as well as by cocapping and comodulation of uPA-R and leukocyte integrins on the monocyte surface. The assemblage of uPA-R, PTKs and membrane spanning beta 2-integrins in one receptor complex indicates functional cooperation. In regard to the involvement of these molecules in pericellular proteolysis, signal transduction, as well as adhesion and chemotactic movement, we suggest uPA-R complex as a potential cellular device for cell migration.


Parkinson's disease: molecular risk factors.
Parkinson's disease (PD) is a progressive neurodegenerative disorder second only to Alzheimer's disease. Diagnosis remains clinical, based on phenotypic patterns. In the last decade many attempts to develop early differential pre-clinical markers have been reported. In this presentation, the molecular risk factors that may link between the etiopathogenesis leading to PD and peripheral markers will be discussed. Genetic variation known to be involved in familial forms of PD will be shown to be linked to sporadic cases, as for example leucine-rich repeat kinase 2 (LRRK2) that was found to regulate microRNA-mediated translation regulation. In addition postmortem microarray findings of transcription alterations will be compared to the peripheral findings of mRNA profiles. Molecular processes involved in ubiquitination and proteasome, autophagy, mitochondrial dysfunction and the nicotinic and adenosine A2 protection will be discussed. The question of what time-point should be used measuring the different markers and the course of the disease considered, and the future possibilities in exploring these techniques will be debated.


A finite element model technique to determine the mechanical response of a lumbar spine segment under complex loads.
This study presents a CT-based finite element model of the lumbar spine taking into account all function-related boundary conditions, such as anisotropy of mechanical properties, ligaments, contact elements, mesh size, etc. Through advanced mesh generation and employment of compound elements, the developed model is capable of assessing the mechanical response of the examined spine segment for complex loading conditions, thus providing valuable insight on stress development within the model and allowing the prediction of critical loading scenarios. The model was validated through a comparison of the calculated force-induced inclination/deformation and a correlation of these data to experimental values. The mechanical response of the examined functional spine segment was evaluated, and the effect of the loading scenario determined for both vertebral bodies as well as the connecting intervertebral disc.